Porth's Essentials of Pathophysiology, 4e

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Mechanisms of Endocrine Control

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the cell membrane. The influx of ions then serves as an intracellular signal to convey the hormone’s message to the interior of the cell. In many instances, the activation of hormone receptors results in the opening of calcium channels, with the increasing intracellular concentration of calcium ions acting as the signal that elicits the cel- lular response. Nuclear Receptors. A second type of receptor mecha- nism is involved in mediating the action of thyroid and steroid hormones, as well as vitamin D, retinoic acid, and other molecules. In contrast to peptide and cate- cholamine hormones, these hormones enter the cell and bind to receptors in the cell nucleus that are gene regula- tory proteins. Many of these hormones and molecules bind to receptors in the cytoplasm, and the hormone– receptor complexes then travel to the nucleus. Nuclear receptors can also be activated by second messenger sig- naling pathways, thereby linking cell surface receptors to nuclear receptor activation pathways. Several subfamilies of nuclear receptors are currently recognized on the basis of structural similarity. One subfamily consists of receptors for thyroid hormone and vitamin D. A second subfamily consists of gluco- corticoid, progesterone, androgen, and estrogen recep- tors. Other subfamilies contain “orphan receptors” for which natural ligands have not as yet been identified. Activated nuclear receptors act by binding to deoxy- ribonucleic acid (DNA) response elements in the pro- moter sites where gene transcription is initiated. These DNA-binding elements, which are termed hormone response elements , then activate or suppress intracellular mechanisms such as gene activity, with the subsequent production or inhibition of mRNA and protein synthe- sis. The importance of the nuclear effects of thyroid and steroid hormones is illustrated by the fact that each reg- ulates protein synthesis. Proteins whose synthesis is reg- ulated up or down by these hormones may be enzymes, structural proteins, receptor proteins, or transcriptional proteins that regulate the expression of other genes, or proteins that are exported from the cell. Some nuclear receptors are regulated by intracellular metabolites rather than secreted signal molecules. The peroxisome proliferator-activated receptors (PPARs), for example, bind intracellular lipid metabolites and regulate the transcription of genes involved in lipid metabolism and adipose tissue metabolism. The thiazoli- dinedione medications, which are used in the treatment of type 2 diabetes mellitus, act at the level of nuclear PPAR- γ receptors to promote glucose uptake and utili- zation by adipose tissue cells (see Chapter 33). Regulation of Hormone Levels Hormone secretion varies widely over a 24-hour period. Some hormones, such as growth hormone (GH) and adre- nocorticotropic hormone (ACTH), have diurnal fluctua- tions that vary with the sleep–wake cycle. Others, such as the female sex hormones, are secreted in a complicated

cyclic manner. The levels of hormones such as insulin and antidiuretic hormone (ADH) are regulated by feedback mechanisms that monitor substances such as glucose (insulin) and water (ADH) in the body. The levels of many of the hormones are regulated by feedback mechanisms that involve the hypothalamic-pituitary–target cell system. Hypothalamic-Pituitary Regulation The hypothalamus and pituitary gland, also known as the hypophysis , form a unit that exerts control over many functions of several endocrine glands as well as a wide range of other physiologic functions. These two structures are connected by blood flow in the hypophy- sial portal system, which begins in the hypothalamus and drains into the anterior pituitary gland, and by the nerve axons that connect the supraoptic and paraven- tricular nuclei of the hypothalamus with the posterior pituitary gland (Fig. 31-4). Hypothalamic Hormones. The synthesis and release of anterior pituitary hormones are largely regulated by the action of releasing or inhibiting hormones from the hypothalamus, which is the coordinating center of the brain for endocrine, behavioral, and autonomic nervous system function. It is at the level of the hypothalamus that emotion, pain, body temperature, and other neural input are communicated to the endocrine system. The poste- rior pituitary hormones, ADH and oxytocin, are synthe- sized in the cell bodies of neurons in the hypothalamus that have axons that travel to the posterior pituitary. The hypothalamic hormones that regulate the secre- tion of anterior pituitary hormones include GH-releasing hormone (GHRH), somatostatin, dopamine, TRH, cor- ticotropin-releasing hormone (CRH), and gonadotro- pin-releasing hormone (GnRH). With the exception of GH and prolactin, most of the pituitary hormones are regulated by hypothalamic stimulatory hormones. GH secretion is stimulated by GHRH; thyroid-stimulating hormone (TSH) by TRH; adrenocorticotropic hormone (ACTH) by CRH; and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by GnRH. The secretion of prolactin, which is also produced by cells in the anterior pituitary gland, is inhibited by dopamine from the hypothalamus. Drugs that interfere with the synthesis or action of dopamine, such as some of the antipsychotic medications, increase prolactin secretion. The activity of the hypothalamus is regulated by both hormonally mediated signals (e.g., negative feed- back signals) and by neuronal input from a number of sources. Neuronal signals are mediated by neurotrans- mitters such as acetylcholine, dopamine, norepineph- rine, serotonin, γ -aminobutyric acid (GABA), and opioids. Cytokines that are involved in immune and inflammatory responses, such as the interleukins, also are involved in the regulation of hypothalamic function (see Chapter 15). This is particularly true of the hor- mones involved in the hypothalamic-pituitary-adrenal axis. Thus, the hypothalamus can be viewed as a bridge by which signals from multiple systems are relayed to the pituitary gland. ( text continues on page 761 )